Human islet-derived, islet-reactive T cells from subjects with Type 1 diabetes

来自 1 型糖尿病患者的人胰岛衍生的胰岛反应性 T 细胞

• 批准号: 9280795
• 负责人: SALLY Choate KENT
• 金额: $ 20.94万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9280795
• 关键词: Activities of Daily Living; Antigen-Presenting Cells; Autoantigens; Autoimmune Process; Autoimmune Responses; B-Lymphocytes; Biological Assay; Blocking Antibodies; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Communication; Cell Line; Cell surface; Cells; Childhood; Cities; Clinical Trials; Clone Cells; Coupled; Diabetes Mellitus; Disease; Engineering; Epitopes; Future; Goals; Histology; Human; Immunohistochemistry; Immunotherapy; In Situ; Inbred NOD Mice; Individual; Infiltration; Innate Immune System; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Left; Lymphocytic Infiltrate; Massachusetts; Methods; Modeling; Modification; Organ Donor; Pancreas; Pathogenesis; Peptides; Peripheral; Phenotype; Post-Translational Protein Processing; Prevention; Proinsulin; Proteins; Reagent; Receptor Cell; Recovery; Regulatory T-Lymphocyte; Reporting; Research Design; Research Personnel; Risk; Rodent Model; Sampling; T-Cell Receptor; T-Lymphocyte; Translating; Translations; United States; Universities; Ursidae Family; autoreactive T cell; autoreactivity; cell type; cytokine; cytotoxicity; design; disorder risk; human disease; human subject; humanized mouse; immunopathology; insight; islet; lymph nodes; medical schools; mouse model; peripheral blood; programs; success; tool; Activities of Daily Living; Antigen-Presenting Cells; Autoantigens; Autoimmune Process; Autoimmune Responses; B-Lymphocytes; Biological Assay; Blocking Antibodies; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Communication; Cell Line; Cell surface; Cells; Childhood; Cities; Clinical Trials; Clone Cells; Coupled; Diabetes Mellitus; Disease; Engineering; Epitopes; Future; Goals; Histology; Human; Immunohistochemistry; Immunotherapy; In Situ; Inbred NOD Mice; Individual; Infiltration; Innate Immune System; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Left; Lymphocytic Infiltrate; Massachusetts; Methods; Modeling; Modification; Organ Donor; Pancreas; Pathogenesis; Peptides; Peripheral; Phenotype; Post-Translational Protein Processing; Prevention; Proinsulin; Proteins; Reagent; Receptor Cell; Recovery; Regulatory T-Lymphocyte; Reporting; Research Design; Research Personnel; Risk; Rodent Model; Sampling; T-Cell Receptor; T-Lymphocyte; Translating; Translations; United States; Universities; Ursidae Family; autoreactive T cell; autoreactivity; cell type; cytokine; cytotoxicity; design; disorder risk; human disease; human subject; humanized mouse; immunopathology; insight; islet; lymph nodes; medical schools; mouse model; peripheral blood; programs; success; tool

PROJECT SUMMARY/ABSTRACT Understanding the autoimmune response in human type 1 diabetes (T1D) is crucial for the design of successful immunotherapies for those at-risk for the disease as well as for those with established disease. While studies of rodent models of have greatly instructed us on the autoimmune process, the translation of successful therapies and prevention studies in the rodent models to human clinical trials has been far less successful. While we know much information concerning islet infiltrating T cells in the rodent models and islet infiltrates in humans with T1D by histology and immunohistochemistry, we previously have not had the opportunity to isolate directly the lymphocytic infiltrate from human with T1D for repertoire analysis and functional capacity. We have received islet isolations from 7 individuals with T1D and have grown or sorted directly out of the islets, 95 CD4 and CD* T cell lines. We have demonstrated the reactivity and HLA restriction of 4 CD4+ T cell lines and 3 CD8+ T cells lines (multiple reactivities are represented). The purpose of this proposal is to assay each T cell line for reactivity to whole normal islets, whole islet proteins, known islet- associated peptide targets of autoreactive T cells, to peptides derived from islet proteins that bear post- translational modifications, to define their HLA restriction, and define their effector functions. These islet- infiltrating T cells will be vital tools/reagents for investigators in the field to study the function of islet-infiltrating T cells in humanized mouse models of T1D, T cell receptor repertoire, to preserve autoreactive T cell receptors for future studies, in functional assays of autoreactive T cell interactions with T regulatory cells, B cell, antigen presenting cells and the innate immune system. Finally, these studies will inform investigators in the design of successful immunotherapies for those at-risk for T1D and especially for those with established T1D.

项目摘要/摘要 了解人类1型糖尿病（T1D）中的自身免疫反应对于设计至关重要 对于那些疾病以及既定疾病的人，成功的免疫疗法。 虽然对啮齿动物模型的研究大大指导了我们自身免疫过程，但翻译的翻译 啮齿动物模型中成功的疗法和预防研究对人类临床试验的差异远远少得多 成功的。虽然我们知道啮齿动物模型和胰岛中有关胰岛渗透T细胞的许多信息 通过组织学和免疫组织化学的人类浸润，我们以前没有 有机会将淋巴细胞浸润与T1D的人类直接分离，以进行曲目分析和 功能能力。我们已经从7个具有T1D的人那里收到了胰岛隔离，并且已经成长或分类 直接从胰岛，95 CD4和CD* T细胞系中。我们已经证明了反应性和HLA限制 4个CD4+ T细胞系和3个CD8+ T细胞系（表示多个反应率）。这个目的 建议是分析每条T细胞系以对整个正常胰岛，全胰岛蛋白，已知胰岛的反应性 自动T细胞的相关肽靶标，与源自胰岛蛋白的肽 翻译修改，定义其HLA限制并定义其效应子功能。这些小岛 - 渗透T细胞将是研究胰岛渗透功能的研究人员的重要工具/试剂 T1D，T细胞受体库的人源化小鼠模型中的T细胞，以保留自动反应性T细胞受体 在未来的研究中，在自动反应性T细胞与T调节细胞，B细胞，抗原相互作用的功能测定中 呈现细胞和先天免疫系统。最后，这些研究将向调查人员提供有关设计的设计 对于T1D，尤其是具有既定T1D的人，成功的免疫疗法。